Synthese achiraler, racemischer und enantiomerenreiner Valproinsäure-Analoga mit antikonvulsiver, neurotoxischer und teratogener Aktivität

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A novel approach to pathogen reduction in platelet concentrates using short-wave ultraviolet light

Background: Transfusion of platelet concentrates (PCs) is the basic treatment for severe platelet disorders. PCs carry the risk of pathogen transmission, especially bacteria. Pathogen reduction (PR) by addition of photochemical reagents and irradiation with visible or ultraviolet (UV) light can significantly reduce this risk. We present a novel approach for PR in PCs employing UVC light alone. Study design and methods: UVC PR was evaluated by bacteria and virus infectivity assays. PC quality was investigated by measuring pH, lactate, glucose, hypotonic shock response, platelet aggregation, CD62P expression, and annexin V binding as in vitro parameters. The impact of UVC PR on the platelet proteome was assessed by differential in-gel electrophoresis and compared with changes caused by UVB and gamma-irradiation, respectively. Results: Vigorous agitation of loosely placed PCs generated thin fluid layers that allow penetration of UVC light for inactivation of the six bacteria and six of the seven virus species tested. HIV-1 was only moderately inactivated. UVC light at the dose used (0.4 J/cm) had a minor impact on in vitro parameters and on storage stability of treated PCs. Proteome analysis revealed a common set of 92 (out of 793) protein spots being affected by all three types of irradiation. Specific alterations were most pronounced for gamma-irradiation (45 spots), followed by UVB (11 spots) and UVC (2 spots). Conclusion: UVC irradiation is a potential new method for pathogen reduction in PCs. The data obtained until now justify further development of this process

Increased human cytomegalovirus replication in fibroblasts after treatment with therapeutical plasma concentrations of valproic acid.

Valproic acid (2-propylpentanoic acid, VPA), an effective inhibitor of histone deacetylases (HDAC) is used for the treatment of epilepsia. In this study, structure-activity relationships for the action of structurally modified VPA derivatives on human cytomegalovirus (HCMV) replication and HDAC inhibition were defined. Pretreatment of human foreskin fibroblasts with VPA (0.125-1mM) caused a concentration-dependent increase of HCMV immediate early and antigen late antigen expression. Structure-activity relationships of VPA derivatives for HCMV stimulation were compared to those for teratogenic action and those for HDAC inhibition. Side chain elongation and introduction of a triple bond in 4-position of the other chain caused teratogenicity, stimulated HCMV replication, and increased HDAC inhibition, as demonstrated by enhanced levels of acetylated histones. Teratogenic VPA derivatives with a branched chain in 3-position as well as a non-teratogenic anticonvulsive active VPA derivative did not stimulate HCMV or accumulation of acetylated histones. This demonstrates a strict correlation between inhibition of HDAC and increased HCMV replication

Inactivation of yellow fever virus in plasma after treatment with methylene blue and visible light and in platelet concentrates following treatment with ultraviolet C light

Background: Yellow fever virus (YFV) is endemic to tropical and subtropical areas in South America and Africa, and is currently a major public health threat in Brazil. Transfusion transmission of the yellow fever vaccine virus has been demonstrated, which is indicative of the potential for viral transfusion transmission. An approach to manage the potential YFV transfusion transmission risk is the use of pathogen inactivation (PI) technology systems, such as THERAFLEX MB-Plasma and THERAFLEX UV-Platelets (Macopharma). We aimed to investigate the efficacy of these PI technology systems to inactivate YFV in plasma or platelet concentrates (PCs). Study design and methods: YFV spiked plasma units were treated using THERAFLEX MB-Plasma system (visible light doses: 20, 40, 60, and 120 [standard] J/cm ) in the presence of methylene blue (approx. 0.8 μmol/L) and spiked PCs were treated using THERAFLEX UV-Platelets system (ultraviolet C doses: 0.05, 0.10, 0.15, and 0.20 [standard] J/cm ). Samples were taken before the first and after each illumination dose and tested for residual virus using a modified plaque assay. Results: YFV infectivity was reduced by an average of 4.77 log or greater in plasma treated with the THERAFLEX MB-Plasma system and by 4.8 log or greater in PCs treated with THERAFLEX UV-Platelets system. Conclusions: Our study suggests the THERAFLEX MB-Plasma and the THERAFLEX UV-Platelets systems can efficiently inactivate YFV in plasma or PCs to a similar degree as that for other arboviruses. Given the reduction levels observed in this study, these PI technology systems could be an effective option for managing YFV transfusion-transmission risk in plasma and PCs

Inactivation of dengue, chikungunya, and Ross River viruses in platelet concentrates after treatment with ultraviolet C light

BACKGROUND Arboviruses, including dengue (DENV 1-4), chikungunya (CHIKV), and Ross River (RRV), are emerging viruses that are a risk for transfusion safety globally. An approach for managing this risk is pathogen inactivation, such as the THERAFLEX UV-Platelets system. We investigated the ability of this system to inactivate the above mentioned arboviruses. STUDY DESIGN AND METHODS DENV 1-4, CHIKV, or RRV were spiked into buffy coat (BC)-derived platelet (PLT) concentrates in additive solution and treated with the THERAFLEX UV-Platelets system at the following doses: 0.05, 0.1, 0.15, and 0.2 J/cm (standard dose). Pre- and posttreatment samples were taken for each dose, and the level of viral infectivity was determined. RESULTS At the standard ultraviolet C (UVC) dose (0.2 J/cm), viral inactivation of at least 4.43, 6.34, and 5.13 log or more, was observed for DENV 1-4, CHIKV, and RRV, respectively. A dose dependency in viral inactivation was observed with increasing UVC doses. CONCLUSIONS Our study has shown that DENV, CHIKV, and RRV, spiked into BC-derived PLT concentrates, were inactivated by the THERAFLEX UV-Platelets system to the limit of detection of our assay, suggesting that this system could contribute to the safety of PLT concentrates with respect to these emerging arboviruses

Reduction of Zika virus infectivity in platelet concentrates after treatment with ultraviolet C light and in plasma after treatment with methylene blue and visible light

BACKGROUNDZika virus (ZIKV) has emerged as a potential threat to transfusion safety worldwide. Pathogen inactivation is one approach to manage this risk. In this study, the efficacy of the THERAFLEX UV-Platelets system and THERAFLEX MB-Plasma system to inactivate ZIKV in platelet concentrates (PCs) and plasma was investigated

Inactivation ofJapanese encephalitis virus in plasma by methylene blue combined with visible light and in platelet concentrates by ultraviolet C light

Background: Japanese encephalitis virus (JEV) is endemic to tropical areas in Asia and the Western Pacific. It can cause fatal encephalitis, although most infected individuals are asymptomatic. JEV is mainly transmitted to humans through the bite of an infected mosquito, but can also be transmitted through blood transfusion. To manage the potential risk of transfusion transmission, pathogen inactivation (PI) technologies, such as THERAFLEX MB‐Plasma and THERAFLEX UV‐Platelets systems, have been developed. We examined the efficacy of these two PI systems to inactivate JEV.Study Design and Methods: Japanese encephalitis virus–spiked plasma units were treated using the THERAFLEX MB‐Plasma system (visible light doses, 20, 40, 60, and 120 [standard] J/cm2) in the presence of methylene blue at approximately 0.8 μmol/L and spiked platelet concentrates (PCs) were treated using the THERAFLEX UV‐Platelets system (UVC doses, 0.05, 0.10, 0.15, and 0.20 [standard] J/cm2). Samples were taken before the first and after each illumination dose and tested for infectivity using an immunoplaque assay.Results: Treatment of plasma with the THERAFLEX MB‐Plasma system resulted in an average of 6.59 log reduction in JEV infectivity at one‐sixth of the standard visible light dose (20 J/cm2). For PCs, treatment with the THERAFLEX UV‐Platelet system resulted in an average of 7.02 log reduction in JEV infectivity at the standard UVC dose (0.20 J/cm2).Conclusions: The THERAFLEX MB‐Plasma and THERAFLEX UV‐Platelets systems effectively inactivated JEV in plasma or PCs, and thus these PI technologies could be an effective option to reduce the risk of JEV transfusion transmissio

Assessment of cross-species transmission of hepatitis C virus-related non-primate hepacivirus in a population of humans at high risk of exposure.

The recent discovery of hepatitis C virus (HCV)-related viruses in different animal species has raised new speculations regarding the origin of HCV and the possibility of a zoonotic source responsible for the endemic HCV transmission. As a consequence, these new findings prompt questions regarding the potential for cross-species transmissions of hepaciviruses. The closest relatives to HCV discovered to date are the non-primate hepaciviruses (NPHVs), which have been described to infect horses. To evaluate the risk of a potential zoonotic transmission, we analysed NPHV RNA and antibodies in humans with occupational exposure to horses in comparison with a low-risk group. Both groups were negative for NPHV RNA, even though low seroreactivities against various NPHV antigens could be detected irrespective of the group. In conclusion, we did not observe evidence of NPHV transmission between horses and humans